Mast Cells in the Developing Brain Determine Adult Sexual Behavior

Abstract

Abstract:Sex differences in brain and behavior are programmed during development by gonadal hormones. We found that the immune system-derived mast cell is a primary target for the masculinizing hormone, estradiol. Male rats had more mast cells in the preoptic area (POA), a brain region essential for male copulatory behavior, during the critical period for sexual differentiation. Activating mast cells in females masculinized POA neuronal and microglial morphology and adult sex behavior, and inhibiting mast cells in males blunted masculinization. Estradiol increased mast cell number and caused mast cells to release histamine, which stimulated microglia to release prostaglandins and thereby induced male-typical synaptic patterning.Inducing an allergic reaction in pregnant dams increased mast cell number in the brains of female fetuses and masculinized neuronal and microglia morphology and adult copulatory behavior. These findings identify a novel non-neuronal origin of brain sex differences and non-steroidal source of variability in brain feminization.

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…The response to local cues is exemplified in the developing preoptic area (POA) where, in males, testosterone is locally aromatized to estradiol and causes POA‐resident mast cells—another immune cell type—to degranulate and release histamine (Lenz et al, ). Estradiol‐induced histamine release occurs during the critical period and is essential for appropriate sexual differentiation of the developing POA.…”

“…In response to local histamine release, microglia in the male POA are predictably more amoeboid than in females (Lenz et al, ). When female pups are masculinized with exogenous estradiol or treated with compounds to induce mast cell degranulation, their microglia phenotype is correspondingly masculinized (i.e., more amoeboid) compared to control females (Lenz et al, , ). As microglia in the neonatal rat POA do not express ERα (Lenz et al, ), sex differences in microglia phenotype must be driven by sex differences in the local microenvironment.…”

“…The male‐specific increase in histamine activates microglial histamine receptors and increases the production of prostaglandin‐E2 (PGE2). Microglia‐derived PGE2 is necessary and sufficient to drive the process of spinogenesis on developing neurons (Lenz et al, , ). By the end of the critical period, male POA neurons will have twice as many dendritic spines, and presumably excitatory synapses, as female neurons, and this synaptic patterning is necessary for the expression of male‐typical copulatory behavior in adulthood (Amateau & McCarthy, , ; Lenz et al, ).…”

“…By the end of the critical period, male POA neurons will have twice as many dendritic spines, and presumably excitatory synapses, as female neurons, and this synaptic patterning is necessary for the expression of male‐typical copulatory behavior in adulthood (Amateau & McCarthy, , ; Lenz et al, ). Any perturbation of this system, either by affecting microglia (i.e., inhibition or depletion) or by altering the environmental cues that drive microglial PGE2 production (i.e., gonadal hormones, mast cell stabilizing drugs, prenatal allergic inflammation) permanently masculinizes female or impairs male rat sex behavior (Lenz et al, , ; Lenz, Pickett, Wright, Galan, & McCarthy, ; VanRyzin et al, ).…”

Elevated zinc transporter ZnT3 in the dentate gyrus of mast cell‐deficient mice

“…Mast cells are granulated immune cells found throughout the body (Ho et al., ; Kempuraj et al., ). In the brain, they are localized in and around the hippocampal formation among other regions and contribute to neuroinflammatory responses (Kempuraj et al., , ) as well as to normal behavioural functioning, such as cognition, emotionality and sexual behaviour (Lenz et al., ; Nautiyal, Ribeiro, Pfaff, & Silver, ; Nautiyal et al., ; Silver & Curley, ). Furthermore, mast cell‐deficient mice have impaired learning and memory, as measured by the Morris water maze and radial arm maze (Nautiyal et al., ).…”